A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas.
A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas.
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HIF1Alpha调节环将缺氧和线粒体信号联系起来。
DOI：
10.1371/journal.pgen.0010008
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发表时间：
2005-07
期刊：
影响因子：
4.5
通讯作者：
Stiles, CD
中科院分区：
文献类型：
--
作者：
Dahia, PLM;Ross, KN;Wright, ME;Hayashida, CY;Santagata, S;Barontini, M;Kung, AL;Sanso, G;Powers, JF;Tischler, AS;Hodin, R;Heitritter, S;Moore, F;Dluhy, R;Sosa, JA;Ocal, IT;Benn, DE;Marsh, DJ;Robinson, BG;Schneider, K;Garber, J;Arum, SM;Korbonits, M;Grossman, A;Pigny, P;Toledo, SPA;Nosé, V;Li, C;Stiles, CD
嗜铬细胞瘤是神经嵴源性肿瘤，由至少6个独立基因的遗传或散发性突变引起。这些基因编码的蛋白质调节不同的功能。我们在这里显示VHL突变的肿瘤和琥珀酸脱氢酶（SDH）亚基B（SDHB）和D（SDHD）编码基因破坏的肿瘤之间的功能联系。在所有这三种肿瘤类型中检测到氧化还原酶的转录谱，以及VHL功能障碍的典型血管生成/缺氧谱。氧化还原酶缺陷，以前没有检测到VHL无效的肿瘤，是由抑制的SDHB蛋白，线粒体复合物II的一个组成部分。在具有SDHD突变的肿瘤中也注意到SDHB的降低。功能获得和功能丧失分析表明，缺氧信号（通过VHL）和线粒体信号（通过SDH）之间的联系是由HIF 1 α介导的。这些发现解释了具有VHL和SDH突变的嗜铬细胞瘤的共同特征，并提出了肿瘤中HIF 1 α活性增加的另一种机制。嗜铬细胞瘤（也称为副神经节瘤）是一种高度血管性的肿瘤，它是由一组不同的、明显无关的肿瘤抑制基因和癌基因突变引起的。作者在这里表明，导致遗传性嗜铬细胞瘤的三个基因具有共同的功能。具体来说，这些基因，VHL，SDHB和SDHD，编码调节称为缺氧诱导因子1亚基α（HIF 1 α）的转录因子的蛋白质，这有助于细胞适应缺氧（低氧水平）。VHL因其在von Hippel-Lindau病（VHL）中的作用而命名，VHL是一种遗传性疾病，使个体易患嗜铬细胞瘤和其他肿瘤。以前的研究表明，当细胞缺乏VHL时，HIF 1 α不会降解，导致类似缺氧的信号。作者发现，导致两种不同的嗜铬细胞瘤综合征的两种基因（基因SDHB和SDHD，编码琥珀酸脱氢酶的亚基B和D，线粒体中能量和呼吸系统的组成酶）的缺失也会引发HIF 1 α反应。研究人员进一步发现，高水平的H1F1 α可以抑制SDHB。这表明一个调节环进一步增强了肿瘤的"缺氧"特征。这一发现为这些不同综合征的共同特征提供了合理的解释，并可能与其他具有显著缺氧模式的癌症相关。
Pheochromocytomas are neural crest–derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1α. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1α activity in tumors. Pheochromocytomas (also known as paragangliomas) are highly vascular tumors that arise from mutations in a diverse and apparently unrelated group of tumor suppressor genes and oncogenes. The authors show here that three of the genes that cause hereditary pheochromocytomas have a common function. Specifically, these genes, VHL, SDHB, and SDHD, encode proteins that regulate a transcription factor known as hypoxia-inducible factor 1 subunit α (HIF1α), which helps cells adapt to hypoxia (low oxygen levels). VHL is named after its role in von Hippel-Lindau disease (VHL), an inherited disorder that predisposes individuals to pheochromocytomas and other tumors. Previous studies showed that when cells lack VHL, HIF1α is not degraded, resulting in a signal that resembles hypoxia. The authors found that loss of two genes that cause two distinct pheochromocytoma syndromes (the genes SDHB and SDHD, which encode the subunits B and D of succinate dehydrogenase, a component enzyme of the energy and respiratory system in mitochondria) also triggers a HIF1α response. The researchers further discovered that high H1F1α levels can suppress SDHB. This suggests a regulatory loop that further enhances the “hypoxia” profile of tumors. This finding provides a rational explanation for the shared features of these distinct syndromes and may be relevant for other cancers with a prominent hypoxic pattern.
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